Plasma Membrane Remodeling During Microglial Activation: A Hypothesis Linking Microglial Shape and Lipid Droplet Formation

Microglia are dynamic cells that respond both transcriptionally and morphologically to acute brain injury as well as to chronic neurodegenerative conditions. Upon activation, they become less ramified, more rounded, and accumulate intracellular lipid droplets. In this hypothesis paper, we propose that the formation of these lipid droplets supports the redistribution of plasma membrane lipids required during morphological remodeling. We rely on original and published studies of microglial morphology under conditions of aging, acute activation, and chronic activation. In ex vivo brain slices, microglia responded to either ATP or acute Aβ injections within minutes by extending their proximal processes toward the stimulus while simultaneously retracting their distal processes into their cell bodies. Chronic exposure to Aβ in mouse models of amyloid reduced microglial branching alongside a two- to three-fold loss of surface area. Transcriptomic analyses showed that activated microglia upregulate genes involved in fatty acid synthesis and fatty acid activation, both processes that are necessary in the production of triacylglycerol. Integrating these new and published analyses of microglia, we developed a hypothesis in which plasma membrane phospholipids are redistributed during acute activation and, during chronic activation, they are metabolized to triacylglycerol into lipid droplets. Tests of this hypothesis, through various pharmacological and genetic approaches, would contribute to our understanding of lipid droplets in cells that undergo substantial morphological changes.